Applicant has previously discovered that microspheres can be prepared from starches, fats, lipid particles, triglycerides, lipoproteins and free fatty acid lipids and these microspheres can be formed with radiopaque materials trapped within. These microspheres were beneficial in visualizing arterial vessels in the body. (U.S. Pat. Nos. 4,680,171 and 5,186,922).
However, there was no suggestion that those prior art microspheres were capable of preferential retention in different types of tissue, and, particularly normal tissue versus a cancerous tumor. Kanke et al. has shown that when polystyrene microspheres are introduced into the blood stream, spheres with diameters greater than 12 .mu.m were predominantly localized in capillaries in the lungs. They have also shown by histologic studies that porous particles of polyglycolic acid (PGA) behave similar to the polystyrene sphere and individual 3- and 5-.mu.m microspheres were found consistently in vascular channels, Kupffer cells, sinusoids of the liver and spleen, and within phagocytizing cells in the bone marrow. (Kanke, M., R. G. Geissler, D. Powell, A. Kaplan and P. P. DeLuca "Interaction of microspheres with blood constituents. III. Macrophage phagocytosis of various types of polymeric drug carriers." Journal of Parenteral Science and Technology 42: 157-65. (1988); Kanke, M., E. Morlier, R. Geissler, D. Powell, A. Kaplan and P. P. Deluca, "Interaction of microspheres with blood constituents II: Uptake of biodegradable particles by macrophages." Journal of Parenteral Science and Technology 40: 114-8 (1986); Kanke, M., I. Sniecinski and P. P. DeLuca, "Interaction of microspheres with blood constituents: I. Uptake of polystyrene spheres by monocytes and granulocytes and effect on immune responsiveness of lymphocytes." J Parenter Sci Technol 37(6): 210-7. (1983).) Others have shown that since hepatic tumors lack Kupffer cells and hepatocytes, unlike the liver, the use of liposomes with an average size of 100-200 nm results in the preferential accumulation of these particles in the liver tissue while being captured less by the tumor (Unger, E. C., P. MacDougall, P. Cullis and C. Tilcock, "Liposomal Gd-DTPA: effect of encapsulation on enhancement of hepatoma model by MRI." Magnetic Resonance Imaging 7:417-23. (1989).) However previous attempts to apply these teachings were limited either by the sizes of liposomes available (Seltzer, S. E., A. S. Janoff, M. Blau, D. F. Adams, S. R. Minchey and L. T. Boni "Biodistribution and imaging characteristics of iotrolan-carrying interdigitation-fusion vesicles." Investigative Radiology 26 Supl 1: S169-71; discussion S175-6 (1991)) or by the poor encapsulation efficiency or the tendency of the microcapsules to leak their contents of previous preparations. (Caride, V. J., H. D. Sostman, R. J. Winchell and J. C. Gore, "Relaxation enhancement using liposomes carrying paramagnetic species." Magn Reson Imaging 2(2): 107-12. (1984).)
Currently available contrast agents for x-ray CT imaging are not optimal for the detection of hepatic tumors. Meticulous use of intravenous liquid contrast material can increase the detection of individual metastatic lesions from 37% to 52%; however, no improvement in sensitivity for detecting abnormalities in normal patients has been achieved by meticulous liquid contrast CT imaging. (Stark, D. D., J. Wittenberg, R. J. Butch and J. T. Ferrucci, Jr., "Hepatic metastases: randomized, controlled comparison of detection with MR imaging and CT." Radiology 165: 399-406. (1987).)
Too many tumors are missed and there is an unacceptable level of false positives since less than 50% of metastatic liver cancers are detected with liquid contrast enhanced CT (Weyman, P. J., Lee, S. K. T., Helken, J. P. et al. "Prospective evaluation of hepatic metastasis: CT scanning, CT angiography, and MRI imaging" (abstr.) Radiology, 161, p. 206 (1986). Accordingly, there is a need for more specific contrast media and delivery techniques which will allow higher detection rates, more specificity and elimination of benign anomalies which occur in otherwise normal individuals.